Naltrexone

Naltrexone is a long-acting opioid receptor antagonist used for relapse prevention in alcohol dependence and for relapse prevention after opioid detoxification. In alcohol dependence it reduces craving and the rewarding effect of drinking. In opioid dependence it blocks the effect of opioids, so patients must be fully opioid-free before starting. Overdose is a risk if a patient stops naltrexone and then returns to a previous opioid dose.

Classification. Opioid receptor antagonist.

Mechanism. Competitive antagonist at mu, kappa and delta opioid receptors, which blocks opioid effects and reduces the reinforcing effect of alcohol.

Pharmacokinetics. Well absorbed orally with extensive first-pass metabolism (bioavailability 5 to 40%). Converted by dihydrodiol dehydrogenase (not CYP enzymes) to the active 6-beta-naltrexol. Half-life of naltrexone about 4 hours and of 6-beta-naltrexol about 13 hours; opioid blockade lasts 24 to 72 hours after a dose.

All oral regimens are given with no loading dose.

Alcohol dependence (after detoxification, to reduce craving and relapse).

• 25 mg on the first day to test tolerance, then 50 mg once daily.
• Duration: usually 3 to 6 months, up to 12 months, with psychosocial support.
• Start while abstinent or when the patient has stopped heavy drinking.

Opioid dependence, relapse prevention after detoxification.

• The patient must be opioid-free for at least 7 to 10 days for short-acting opioids and at least 10 to 14 days for long-acting opioids such as methadone, confirmed by a negative urine opioid screen and, if there is doubt, a naloxone challenge.
• Start 25 mg once daily; if no withdrawal after 1 hour, give a further 25 mg to reach 50 mg on day 1.
• Maintenance 50 mg once daily, or 100 mg on alternate days, or 150 mg every third day to improve supervised adherence.

Extended-release injection (where available). 380 mg intramuscular into the gluteal muscle every 4 weeks.

Dose limits. Liver impairment: use cautiously; avoid in acute hepatitis or liver failure. Kidney impairment: use cautiously in moderate to severe impairment. Doses over 50 mg daily raise the risk of liver injury.

Contraindications. Acute hepatitis or liver failure, current opioid use or dependence, opioid withdrawal, positive urine opioid screen, need for opioid analgesia, hypersensitivity.

Serious adverse effects. Hepatocellular injury (dose-related), precipitated opioid withdrawal, opioid overdose after stopping naltrexone or attempting to overcome the blockade, depression or suicidal thoughts, injection site reactions (severe, with extended-release injection).

Common adverse effects. Nausea, vomiting, headache, dizziness, insomnia, anxiety, fatigue, abdominal pain, reduced appetite, joint and muscle pain.

Interactions. Opioid analgesics, opioid cough preparations and opioid antidiarrhoeals (codeine, loperamide in high doses) are blocked or may be ineffective. Thioridazine causes lethargy. Disulfiram adds liver toxicity. Alcohol is not an interaction in itself, but alcohol-related liver disease needs to be checked.

Common prescribing errors. Starting before the opioid washout is complete; not checking liver function; forgetting to warn about loss of opioid tolerance; prescribing for patients who need opioid pain relief; using alone without psychosocial support.

Special groups.

• Pregnancy: avoid unless the benefit clearly outweighs the risk; limited data.
• Breastfeeding: avoid.
• Children: not established.
• Older adults: use with caution.
• Kidney impairment: use cautiously.
• Liver impairment: avoid in acute hepatitis or failure; use cautiously otherwise.

Formulations. Tablets 50 mg; extended-release injectable suspension 380 mg in some regions. Take with food to reduce nausea.

Baseline. Liver function tests, urine opioid screen, pregnancy status, hepatitis B and C and HIV status where relevant, history of depression, time since last opioid use, medicines list.

Monitoring. Repeat liver function tests monthly for 3 months and then every 3 months. Review mood, craving, adherence and alcohol or opioid use at each visit. Give a card that says the patient takes an opioid blocker.

Stopping. No taper is needed. Warn that tolerance to opioids is lost within days and that returning to a previous opioid dose can cause fatal overdose. For elective surgery, stop oral naltrexone at least 72 hours before and stop the extended-release injection at least 4 weeks before if opioid analgesia is likely to be needed.

Referral and escalation. Refer to addiction services for opioid dependence and for patients who relapse. Jaundice, dark urine, severe abdominal pain, or suicidal thoughts needs the drug stopped and urgent assessment.